Novel antagonists for proteinase-activated receptor 2: inhibition of cellular and vascular responses in vitro and in vivo.

BACKGROUND AND PURPOSE: Proteinase-activated receptor 2 (PAR(2)) is a G-protein coupled receptor associated with many pathophysiological functions. To date, the development of PAR(2) antagonists has been limited. Here, we identify a number of novel peptide-mimetic PAR(2) antagonists and demonstrate inhibitory effects on PAR(2)-mediated intracellular signalling pathways and vascular responses. EXPERIMENTAL APPROACH: The peptide-mimetic compound library based on the structures of PAR(2) agonist peptides were screened for inhibition of PAR(2)-induced calcium mobilisation in human keratinocytes. Representative compounds were further evaluated by radioligand binding and inhibition of NFkappaB transcriptional activity and IL-8 production. The vascular effects of the antagonists were assessed using in vitro and in vivo models. KEY RESULTS: Two compounds, K-12940 and K-14585, significantly reduced SLIGKV-induced Ca(2+) mobilisation in primary human keratinocytes. Both K-12940 and K-14585 exhibited competitive inhibition for the binding of a high-affinity radiolabelled PAR(2)-ligand, [(3)H]-2-furoyl-LIGRL-NH(2), to human PAR(2) with K(i) values of 1.94 and 0.627 microM respectively. NFkappaB reporter activity and IL-8 production were also significantly reduced. Furthermore, relaxation of rat-isolated aorta induced by SLIGRL-NH(2) was inhibited competitively by K-14585. K-14585 also significantly lowered plasma extravasation in the dorsal skin of guinea pigs and reduced salivation in mice. CONCLUSIONS AND IMPLICATIONS: K-12940 and K-14585 antagonized PAR(2) competitively, resulting in inhibition of PAR(2)-mediated signalling and physiological responses both in vitro and in vivo. These peptide-mimetic PAR(2) antagonists could be useful in evaluating PAR(2)-mediated biological events and might lead to a new generation of therapeutically useful antagonists.

[Women, AIDS and society]. / Femmes, SIDA et societe

PIP: Heterosexual transmission of AIDS is the major means of transmission in Zaire followed by contaminated blood banks and perinatal transmission. The majority of women infected by AIDS are those between 20-40 who are sexually active, candidates for maternity, unwanted pregnancies and abortions. In Kinshasa, 4-7% of pregnant women are HIV positive as compared to rural women (2.2-3%). The SIDA Project in Kinshasa has shown that vertical transmission (VT) from mother to child is 39% with 20% of infected infants dying before age 1. The HIV virus has increased infant mortality by 15% which has diminished between 1950-85 to 107 from 157. A positive HIV diagnoses for their baby is generally a woman's 1st exposure to AIDS in Zaire making the women more vulnerable in a society where she may be rejected by her family and community. Prostitutes constitute a high risk group; there is a 40% seroprevalence in Kinshasa, and most women are not protected during sex. Results from a survey by Project SIDA showed that 10% of prostitutes who were negative had stable partners who were positive. The impact of AIDS on Zairian women has affected the relationship of the family because women are responsible for the care of children. Yet women in Zaire and in all of SSA are 80% illiterate and they do not have access to information. The social problem is compounded by the lack of IEC and social services that can provide counseling, financial help and medical help to young mothers infected with AIDS who are dying.^ieng

Comparison of sensitivities and specificities of latex agglutination and an enzyme-linked immunosorbent assay for detection of antibodies to the human immunodeficiency virus in African sera.

The sensitivities, specificities, and positive and negative predictive values of the Cambridge BioScience Corp. (Worcester, Mass.) human immunodeficiency virus latex agglutination assay were compared by using three different blood preparations. By using the manufacturer's standard test method with diluted sera, the sensitivity of latex agglutination was 100%, the specificity was 99.58%, and the positive and negative predictive values were 99.26 and 100%, respectively. Use of diluted whole blood or undiluted whole blood did not significantly affect the sensitivity (mean, 99.72%), specificity (mean, 99.47%), positive predictive value (mean, 99.07%), or negative predictive value (mean, 99.89%). The latex agglutination assay is a simple, rapid assay for the detection of human immunodeficiency virus that would be useful in Third World countries or other areas where enzyme-linked immunosorbent assays are not available or cannot be used.